In recent years, causes of diseases or dermal injuries or diseases brought about by an oxidative stress such as ultraviolet rays, active oxygen, free radicals or the like have been searched briskly. For example, it is known that cytotoxic cytokines such as IL-1α, TNF-α and the like or extracellular matrix proteases such as collagenase and the like are closely related to aging, canceration or malignant alteration, edema, pigmentation or the like as its cause (for example, “Oxidative Stress in Dermatology”, Marcel Dekker, Inc., pp. 187–205, 1993). Expression of a gene coding for such a protein is mainly controlled at the level of genetic transcription, whereas, regarding cytotoxic proteins such as cytotoxic cytokines and extracellular matrix proteases, it is controlled by a transcriptional regulatory factor such as NF-κB or AP-1 (for example, “Active oxygen and Signal transmission”, Kodansha Scientific, pp. 37–46, 1996). In practice, NF-κB and AP-1 are known to be activated by an oxidative stress and promote the expression of cytotoxic protein (for example, “Active oxygen and Signal transmission”, Kodansha Scientific, pp. 1–20, 1996). Diseases or dermal injuries or diseases caused by an oxidative stress are therefore expected to be prevented, retarded, alleviated or treated if it becomes possible to suppress the activation of NF-κB or AP-1 due to an oxidative stress.
There is a description that the activation of NF-κB is inhibited by a sulfur-containing antioxidant such as N-acetyl-L-cysteine or pyrrolidine dithiocarbamate (for example, “Active oxygen and Signal transmission”, Kodansha Scientific, pp. 37–46, 1996). It is reported that N-acetyl-L-cysteine can also suppress the activation of AP-1 (for example, “FEBS Letters”, Vol. 384, pp. 92–96, 1996). These compounds are, however, accompanied with such drawbacks as insufficient effects or strong cytotoxicity. Sulfur-containing compounds such as N,N′-diacetyl-L-cystine are known to suppress dermal inflammation induced by leukotrienes (ex. U.S. Pat. No. 4,827,016), but not known to inhibit cytokines or transcription factor taking part in aging, canceration, edema, pigmentation or the like. In addition to sulfur-containing antioxidants, there are reports on retinoic acid used for inhibiting the activation of AP-1 and the expression of extracellular matrix proteases (for example, “Nature”, Vol. 379, pp. 335–339, 1996); and steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs used for suppressing the activation of NF-κB (for example, “Bio Essays”, Vol. 18, pp. 373–378, 1996). Retinoic acid and steroidal anti-inflammatory drugs are not free from side effects such as detachment of the skin and steroid-induced skin diseases, respectively, so that they cannot be used freely. Non-steroidal anti-inflammatory drugs do not cause systemic side effects which are observed upon use of a steroidal anti-inflammatory drug, but there is room for improvement in its local side effects. In addition, its effects for suppressing the activation of inflammatory factors are insufficient.
As one of the diseases or dermal injuries or diseases caused by an oxidative stress, a change in the skin due to aging or an undesirable esthetic change in the skin can be mentioned. It is reported that in order to prevent or retard such a change, a natural extract having action for alleviating skin roughness or the component contained therein, such as astaxantin, and a cystine derivative are in combination applied to the skin (for example, Japanese Patent Application Laid-Open (Kokai) No. Hei 9-143,063). According to the report, such a combination contributes to the recovery of resilience or luster of the skin or the amelioration of the somber coloring, but does not exhibit sufficient effects. In addition, its effects against skin wrinkles or flabby skin, the most eminent symptoms in the observation of the aged skin, are, however, not revealed.
Induction or promotion of skin wrinkles or flabby skin is a typical example of skin change due to aging or an undesirable aesthetic skin change, both brought about by an oxidative stress. The sun light or ultraviolet rays therefrom can be mentioned as its cause (for example, “Shin Keshohin-gaku”, Nanzando, pp. 38–46, 1993). As a method for preventing or retarding such a change, application of an antioxidant such as tocopherol, ascorbic acid, N-acetyl-L-cysteine or the like to the kin is reported (for example, “Photodermatol. Photoimmunol. Photomed., Vol.7, pp. 56–62, 1990 or Japanese Language Laid-Open Publication (PCT) No. Hei 6-510,542). Prevention or retardation is also effected by the application of an anti-inflammatory drug or an ultraviolet absorber, other than an antioxidant (for example, “Photodermatol. Photoimmunol. Photomed., Vol.7, pp. 153–158, 1990 or J. Photochem. Photobiol. B: Biol., Vol. 9, pp. 323–334, 1991) or improvement is conducted using retinoic acid (for example, “J. Invest. Dermatol., Vol. 98, pp. 248–254, 1992). These compounds are, however, accompanied with the problems such as insufficient effects, strong cytotoxicity and low light stability. Moreover, anti-inflammatory drugs and retinoic acid are not free from side effects as described above.